In recent years, there have been appeared many scientific reports indicating that the replacement of H to Cl, Br or I atoms may even led to the several hundred-fold increase in affinity of the compound to the biological target and is associated with non classic interactions in the binding site of the receptor, called halogen bonds. The main objective of the proposed project is to evaluate the role of halogen bonds in the interaction of ligands with selected receptors of family A GPCRs.
The main hypothesis concerns that the affinity of the compound is driven by switch on the additional energy contribution coming from created halogen bonds in a ligand-receptor complexes. In addition, the influence of the position and type of halogen atoms and modification of the molecular core to the strength of halogen bonding will be studied.
In order to find answers to the problem highlighted in the subject of the project, the mechanism of interaction of compounds with determined biological activity, but differing only in the type of halogen substituent with a selected crystals of family A GPCR and homology models of three not crystallized (5-HT1A, 5-HT6, 5-HT7) will be performed based on the detailed analysis of docking results (Task 1). For this purpose, the following computational methods will be used: QPLD molecular docking (Quantum-Polarized Ligand Docking) and QM/MM simulations.
The next stage of the project will be to design and synthesized of (Task 2) about 80 new halogenated analogues for at least five initial chemotypes (three of which were selected in the preliminary study) having an average biological activity. The amino acids identified in the preliminary studies as a crucial in the formation of halogen bonds will be used as constraints in the evaluation of compounds to the synthesis. These compounds will be derived from a combinatorial library generated on the basis of synthetic pathway for initial chemotypes, and halogenated derivatives of commercially available reagents. Synthesis of compounds will be performed in the Department of Medicinal Chemistry IP PAS, and in the Department of Medicinal Chemistry, Jagiellonian University. In addition, commercial libraries of chemical compounds will be searched for identify halogenated analogs (20 million compounds from e.g. Enamine, ChemDiv, ChemBridge, UORSY companies) on the basis of virtual screening procedure developed for 5-HT1A, 5-HT6 and 5-HT7 in DMC IP PAS. About 100 compounds will be carefully selected and ordered. Predicted on the basis of molecular modeling relationships for designed derivatives will be verified on in vitro studies (Task 3) and SAR analysis. The Task 4 consists in analysis of all results in order to check hypotheses, determine the role and attempt to explain the mechanism of the halogen bonds formation in the family A GPCRs.
Expected impact of the project on the development of science, civilization and society
To date, any systematic and comprehensive studies on the role and significance of halogen bonds in family A GPCRs have been published. There is also no studies showing the use of the concept of halogen bonds in the rational design of potential ligands of these receptors.
The results of the planned study will expand existing knowledge on the role of the halogen bonds in the ligand-receptor interactions and allow for: the broad analysis of the binding pocket of not crystallized receptors of family A GPCRs (5-HT1A, 5-HT6 and 5-HT7), improving the molecular modelling tools (pharmacophore models, pharmacophore fingerprint, analysis of docking results), and the development of synthesis routes of new chemotypes on solid phase.
Rafał Kurczab, PhD
phone: +4812 66 23 301
Krzysztof Rataj, MSc
phone: +4812 66 23 301
Adam Hogendorf, MSc
phone: +4812 66 23 320
Grzegorz Satała, PhD
phone: +4812 66 23 301
Vittorio Canale, PhD
Paweł Zajdel, PhD
- Kurczab R., Canale V., Satała G., Zajdel P., Bojarski A. J., Amino Acid Hot Spots of Halogen Bonding–a Combined Theoretical and Experimental Case Study of the 5-HT7 Receptor. J. Med. Chem. 2018, acs.jmedchem.8b00828,
- Partyka, A; Kurczab, R; Canale, V; Satała, G; Marciniec, K.; Pasierb, A.; Jastrzębska-Więsek, M.; Pawłowski, M.; Wesołowska, A.; Bojarski, A. J.; Zajdel, P.; The impact of the halogen bonding on D2 and 5-HT1A/5-HT7 receptor activity of azinesulfonamides of 4-[(2-ethyl)piperidinyl-1-yl]phenylpiperazines with antipsychotic and antidepressant properties, Bioorg. Med. Chem. 2017, 25, 3638–3648,
- Kurczab, R.; The evaluation of QM/MM-driven molecular docking combined with MM/GBSA calculations as a halogen bond scoring strategy. Acta Crystalographica B, 2017, 73, 188–194.
- Hogendorf, A.S.; Hogendorf, A.; Kurczab, R.; Satała, G.; Lenda, T.; Walczak, M.; Latacz, G.; Handzlik, J.; Kieć-Kononowicz, K.; Wierońska, J.M.; Woźniak, M.; Cieślik, P.; Bugno, R.; Staroń, J.; Bojarski, A.J. Low-basicity 5-HT7 Receptor Agonists Synthesized Using the van Leusen Multicomponent Protocol. Sci Rep. 2017, 7, 1444.
- Staroń, J.; Warszycki, D.; Kurczab, R.; Satała, G.; Bugno, R.; Hogendorf, A.; Bojarski, AJ. Halogen Bonding Enhances Activity in a Series of Dual 5-HT6/D2 Ligands Designed in a Hybrid Bioisostere Generation/virtual Screening Protocol. RSC Adv. 2016, 6, 54918–54925.
b) participation in conferences:
- Kurczab, R.; The significance of halogen bonding in ligand-receptor interactions – the lesson learned from Molecular Dynamic simulations of D4 receptor, IXth Conversatory on Medicinal Chemistry, 13–15.09.2018, Lublin, Poland, Book of Abstracts P-66,
- Kurczab, R.; Lessons learned from the experimental and theoretical study of halogen bonding in the class A GPCRs, Modeling and Design of Molecular Materials, 24–28.06.2018, Polanica Zdrój, Poland, Book of Abstracts P-29B,
- Canale, V.; Satała, G.; Bojarski, A.J.; Zajdel, P.; Kurczab, R. Wiązania halogenowe w racjonalnym projektowaniu ligandów receptora 5-HT7 w grupie arylosulfonamidowych pochodnych (aryloksy)etylopiperydyn. XXIII Naukowy Zjazd PTFARM, 19–22.09.2017, Cracow, Poland, Book of Abstracts, P-104,
- Kurczab, R.; Different roles of halogen substituents in ligand-receptor interactions – a class A GPCRs case study, 10th Joint Meeting of Medicinal Chemistry, 25-28.06.2017, Dubrovnik, Croatia, Book of Abstracts, P-74.
- Kurczab, R.; Bojarski, AJ.; The potential role of halogen bonding in interactions of ligands with class A GPCRs – the β2 adrenergic receptor case study, VIIth Conversatory on Medicinal Chemistry, 17-19.09.2015, Lublin, Poland, Book of Abstracts, P-58.
c) oral communications
- Kurczab, R. Evaluation of halogen bonding hot spots by virtual screening of commercial databases – a case study of 5-HT7R, 10th Joint Meeting of Medicinal Chemistry, 25–28.06.2017, Dubrovnik, Croatia, Book of Abstracts, OP9.
- Kurczab, R. Wiązania halogenowe – od struktury krystalograficznej do racjonalnego projektowania nowych leków, XXXIV Szkoła Zimowa Instytutu Farmakologii PAN w Krakowie, 10–12.01.2017, Cracow, Poland.
- Canale, V.; Satała, G.; Bojarski, A.J.; Zajdel, P.; Kurczab, R. Halogen bonding in the rational design of 5-HT7 receptor ligands in a group of arylsulfonamide derivatives of (aryloxy)ethyl piperidines Young Research Fellow Meeting, 08–10.02.2017, Châtenay-Malabry, France, Book of Abstracts, OC-001.
- Kurczab, R; The potential of halogen bonding in class A of GPCRs: application of XB hot spots for rational design of 5-HT7R ligands, VIIIth Conversatory on Medicinal Chemistry, 15-17.09.2016, Lublin, Poland, Book of Abstracts, C-6.
- Kurczab, R.; Rataj, K.; Bojarski, AJ.; Halogen bonding – the role and significance in interaction of ligands with class A GPCRs, 2nd International Symphosium on Halogen Bonding, 6–10.06.2016, Gothenburg, Sweden, Book of Abstract, YR05
The study is supported by a grant SONATA UMO-2014/15/D/NZ7/01782 financed by the National Science Centre